Process for converting S-enantiomer to its racemic form

ABSTRACT

The present invention relates to a novel process for converting the unwanted S enantiomer form to its useful raceme with respect to a 4-aminoindane derivative.

TECHNICAL FIELD

The present invention relates to the compound7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine (the “Comp II”),an intermediate useful for the preparation of the fungicidal compound3-difluoromethyl-N-(7-fluoro-1,1,3-trimethyl-4-indanyl)-1-methyl-4-pyrazolecarboxamide(the “Comp I”). More particularly, the present invention relates to theS enantiomer of Comp II and the preparation thereof. The formulas ofComp I and II are as follows:

BACKGROUND OF THE INVENTION

The Comp I is a recently discovered fungicidal molecule. The patentapplication WO2012084812 by Venturini, Isabella et al, first describedthe Comp I as a fungicide for agricultural use and the synthesisthereof. Structurally, the Comp I is an amide compound and thus can beeasily obtained by the routine processes for making those amidecompounds. For example, the Comp I can be obtained by condensing theComp II and a corresponding pyrazole carboxylic acid or pyrazolecarboxylic acid halide which provides the corresponding indane portionof the resultant Comp I. The synthesis route is showed as follows:

The Comp I is a chiral molecule with a chiral central on the 3′-carbonof the indane ring, which makes the Comp I have two enantiomer forms,namely R and S enantiomers. Further investigation found that the Renantiomer is the active component contributing to the fungicidalactivity, while the S enantiomer shows no or less fungicidal activity.

Thus, there is a desire to synthesize in high yield the active componentof R enantiomer without the formation of the unwanted inactive Senantiomer. One currently used approach to achieve this goal is usingthe R enantiomer of Comp II instead of the racemic form thereof as thestarting material to react with the corresponding indane derivative tospecifically yield the desired R enantiomer. With this approach, the Renantiomer of Comp II is useful while the S enantiomer is useless andwasted.

There is still a strong need to be met where the inactive S enantiomercan be recycled and the active R enantiomer can be synthesized in highyield.

SUMMARY OF THE INVENTION

That need is well fulfilled by the present invention. Thus, in oneaspect of the present invention, it provides a novel process for thepreparation of(R,S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine, startingwith (S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine, or tosay a process for converting(S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine to its racemicform, namely(R,S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine.

The presently claimed process mainly comprises the steps of:

(a) acylating the(S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine to obtain anindaneamide derivative;

(b) oxidizing said indaneamide derivative to obtain 3-hydroxylindaneamide derivative;

(c) dehydrating said hydroxyl indaneamide derivative to obtainindeneamide derivative;

(d) deacylating said indeneamide derivative to obtain indene aminederivative; and

(e) hydrogenating said indene amine derivative to obtain the desired(R,S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine.

In another aspect of the present invention, it provides a process fullysame to the aforesaid one except that the dehydration step (c) iscarried out prior to subsequent to the deacylation step (d), or thesetwo steps are carried out concurrently.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a novel process for the preparation of(R,S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine (“FormulaI”), starting with(S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine (“FormulaII”). The Formula I and II as well as the entire synthesis route areshown below:

wherein, R is defined as below.

Thus, in one aspect, the present invention provides a process for thepreparation of(R,S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine, comprisingthe following steps of:

(a) acylating the(S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine to obtain anindaneamide derivative;

(b) oxidizing said indaneamide derivative to obtain hydroxyl indaneamidederivative;

(c) dehydrating said hydroxyl indaneamide derivative to obtainindeneamide derivative;

(d) deacylating said indeneamide derivative to obtain indene aminederivative; and

(e) hydrogenating said indene amine derivative to obtain the desired(R,S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine.

In another aspect, the present invention provides a process for thepreparation of(R,S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine having thefollowing Formula I, comprising the following steps of:

(a) acylating (S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-aminehaving the following Formula (II) with an acylating agent of FormulaRC(O)X to give a corresponding indaneamide derivative of Formula (III);

(b) oxidization of said indaneamide derivative to give the correspondinghydroxyl indaneamide derivative of Formula (IV)

(c) dehydration of said hydroxyl indaneamide derivative to give thecorresponding indeneamide derivative of Formula (V);

(d) deacylation of said indeneamide derivative to give the correspondingindeneamine derivative of Formula (VI); and

(e) hydrogenation of said indeneamine derivative to obtain the desired(R,S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine,

wherein,

-   -   R is selected from a C₁-C₆ alkyl group or a C₆-C₁₀ aryl group,        these groups being optionally substituted with one or more of        C₁-C₆ alkyl groups and/or halogen atoms;    -   X is a leaving group selected from: (i) a hydroxy group; (ii) a        halogen atom; (iii) a C₁-C₆ alkylsulfonyloxy group; (iv) a        C₆-C₁₀ arylsulfonyloxy group, (v) a R_(a)COO group wherein R_(a)        is a C₁-C₆ alkyl group, the groups (iii)-(v) being optionally        substituted with one or more halogen atoms.

Examples of a C₁-C₆ alkyl group are methyl, ethyl, propyl, butyl,pentyl, hexyl.

Examples of a C6-C10 aryl group are phenyl, naphthyl.

Examples of halogen atoms are fluorine, chlorine, bromine, iodine.

The process of the present invention is carried out in the order asindicated above.

In one embodiment of the present processes, the order of the reactionsbetween dehydration step (c) and deacylation step (d) can be changed. Inanother embodiment, step (c) is carried out prior to or subsequent tostep (d). In a further embodiment, step (c) and step (d) are carried outconcurrently.

In one embodiment, in step (a) of the present invention, the acylatingagent RC(O)X for illustrative purpose is selected from acyl halide andanhydride, preferably acyl halide and anhydride of a lower alkanoicacid, more preferably selected from acetyl chloride, acetic anhydride ormixture thereof. However, one skilled in the art will appreciate thatnumerous alternative acylating agents can be used interchangeably instep (a) In another embodiment, the step (a) is carried out at elevatedtemperature, preferably ranging from about 80° C. to about 120° C., morepreferably ranging from about 80° C. to about 100° C. In anotherembodiment, step (a) comprises adding the compound of Formula (II) tofreshly distilled acetic anhydride.

In one embodiment, in step (b) of the present invention, the oxidizationcomprises reacting the indaneamide derivative of Formula (III) in thepresence of oxidizing agent to yield the corresponding hydroxylindaneamide derivative of Formula (IV). In another embodiment, theoxidizing agent for illustrative purpose is selected from the groupconsisting of KMnO₄, MnO₂, SeO₂, CrO₃, or mixture thereof, preferablyKMnO₄. The skilled one in the art will appreciate numerous alternativeoxidizing agent can be used interchangeably in step (b) of the presentinvention. In another embodiment, the reaction of step (b) is carriedout at room temperature under stirring, preferably in the presence ofMgSO₄.

In one embodiment, in step (c) of the present invention, the dehydrationcomprises reacting said hydroxyl indaneamide derivative of Formula (IV)in the presence of a strong acid to yield indeneamide derivative offormula (V). In another embodiment, the reaction is carried out in anorganic solvent, preferably selected from hexane, heptanes, methylenechloride, dichloroethane, methanol, ethanol, isopropanol, toluene, ethylacetate and mixtures thereof. In another embodiment of step (c), thestrong acid is selected from the group consisting of HCl, HBr, H₂SO₄ ormixtures thereof, with con. HCl and H₂SO₄ more preferred. In anotherembodiment, the reaction is carried out at room temperature, preferablyranging from about 20° C. to about 40° C., more preferably about 25° C.In another embodiment, the reaction is carried out at elevatedtemperature under stirring. In another embodiment, the reaction of step(c) is carried out without solvent.

In one embodiment, in step (d) of the present processes, the deacylatingcomprises contacting said indeneamide derivative with a strong acid,under elevated temperature to give an addition salt of indeneaminederivative; and then said indeneamine is treated with a base solution,to yield the indeneamine of Formula (VI). In another embodiment, for theillustrative example the strong acid is selected from the groupconsisting of HCl, HBr, H₂SO₄ or mixtures thereof, with con. HCl andH₂SO₄ more preferred. In another embodiment, the reaction is carried outat the elevated temperature ranging from about 90° C. to about 120° C.,preferably ranging from about 100° C. to about 120° C. In anotherembodiment, the base is selected from NaOH, NaHCO₃, KOH and mixturesthereof.

In one embodiment, in step (e) of the present invention, thehydrogenation comprises reacting said indeneamine derivative withgaseous hydrogen in the presence of a hydrogenation catalyst, to obtainthe desired (R,S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine.In another embodiment, the reaction is carried out in an organicsolvent, preferably a polar solvent, more preferably selected fromhexane, heptanes, methylene chloride, dichloroethane, methanol, ethanol,isopropanol, toluene, ethyl acetate and mixtures thereof. Theillustrative examples of the hydrogenation catalyst include Group (X)metal catalysts, such as nickel, palladium and platinum, preferably Pd—Ccatalyst. In another embodiment, the reaction of step (e) is carried outwithout solvent.

In another aspect of the present invention, it provides a racemate of(R,S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine which isprepared according to the present claimed processes.

In a further aspect of the present invention, it provides a compound ofFormula V, where the R group is defined as above in the presentapplication. In one embodiment, the present invention provides acompound of N-(7-fluoro-1,1,3-trimethyl-1H-inden-4yl)acetamide.

In a further aspect of the present invention, it relates to use of thecompound of Formula V for the preparation of(R,S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine. In oneembodiment, it relates to use ofN-(7-fluoro-1,1,3-trimethyl-1H-inden-4yl)acetamide for the preparationof (R,S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine.

In a further aspect of the present invention, it relates to a compoundof Formula IV where the R group is defined as above in the presentapplication. In one embodiment, the compound of Formula IV is(S)—N-(7-fluoro-1,1,3-trimethyl-3-hydroxy-1H-indan-4-yl)acetamide.

In a yet further aspect of the present invention, it provides a compoundof Formula VI, 7-fluoro-1,1,3-trimethyl-1H-inden-4-amine.

The advantages of the presently claimed invention as described above areapparent to the skilled one in the art. With the processes of thepresent invention, the unwanted(S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine can beconverted back to its raceme form and further recycled to produce thedesired active form of R enantiomer. Therefore, the present process ismore environmentally friendly and more cost effective which was neverreported or envisioned before.

The following examples are provided for illustrative purpose, and shallnot be construed in any way to restrict the scope of the presentlyclaimed invention.

EXAMPLES Example 1 Step (a)—Acylation: Preparation of(S)—N-(7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)acetamide ofFormula (III)

(S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine (6 g, 31 mmol)was added to freshly distilled acetic anhydride (4 mL) and stirred at90° C. for 30 min. Upon completion, reaction mixture was cooled to roomtemperature and was quenched by water (20 ml). The reaction mixture wasextracted with ethyl acetate (50 mL). The organic layer was dried overNa2SO4 and concentrated in vacuo to leave a crude solid of(S)—N-(7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)acetamide (7.1g) that was analyzed by GC: 97.5%.

Step (b)—Oxidization: Preparation of(S)—N-(7-fluoro-1,1,3-trimethyl-3-hydroxy-1H-indan-4-yl)acetamide ofFormula (IV)

15% MgSO4 solution was prepared (4.6 g, 38 mmol). To this solution(S)—N-(7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl)acetamide (6g, 25.5 mmol) obtained from Step (a) dissolved in acetone (90 mL) wasadded at room temperature. To this solution KMnO₄ (9.26 g, 58.6 mmol) insolid form was added in portions and stirred at room temperature for 5hours. Upon completion, reaction mixture was quenched by 1N NaOHsolution to basic pH. The reaction mixture was extracted with ethylacetate (50 mL). The organic layer was dried over Na₂SO₄ andconcentrated in vacuo to leave a crude solid of(S)—N-(7-fluoro-1,1,3-trimethyl-3-hydroxy-1H-indan-4-yl)acetamide (5.1g) that was analyzed by GC: 83.5% A.

Step (c)—Dehydration: Preparation ofN-(7-fluoro-1,1,3-trimethyl-1H-inden-4yl)acetamide of Formula (V)

Methanol (30 mL) was added to(S)—N-(7-fluoro-1,1,3-trimethyl-3-hydroxy-1H-indan-4-yl)acetamideobtained from Step (b) (5g, 19.8 mmol). To this solution conc. HCl (10mL) was added at room temperature and stirred for 90 min. The reactionmixture was diluted with water (100 mL) and extracted with ethyl acetate(50 mL). The organic layer was dried over Na₂SO₄ and concentrated invacuo to leave a crude solid ofN-(7-fluoro-1,1,3-trimethyl-1H-inden-4yl)acetamide (4g) that wasanalyzed by GC: 90.8% A.

Step d—Deacetylation: Preparation of7-fluoro-1,1,3-trimethyl-1H-inden-4-amine of Formula (VI)

25g of 50% H₂SO₄ was added toN-(7-fluoro-1,1,3-trimethyl-1H-inden-4yl)acetamide obtained from Step(c) (4g, 17.2 mmol) at room temperature. The reaction mixture wasstirred at 115° C. for 5 h. The reaction mixture was then diluted to 25%by adding water. Resulted solids were filtered, washed with water andthen with hexane. The resulted solids were added to water (20 mL),basified with 10% NaOH solution (15 mL) and stirred at room temperaturefor 1 h. The reaction mixture extracted with ethyl acetate (20 mL). Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo to leave acrude solid of 7-fluoro-1,1,3-trimethyl-1H-inden-4-amine (2.2g) that wasanalyzed by GC: 95.5% A.

Step e—Hydrogenation: Preparation of(R,S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine of Formula(I)

Methanol (20 mL) was added to 7-fluoro-1,1,3-trimethyl-1H-inden-4-amineobtained from Step (d) (1g, 7.6 mmol). To this solution 10% Pd—C (50 mg,0.05 mmol) was added at room temperature. Dry hydrogen gas was bubbledthrough gas bubbler at room temperature under stirring for 2 h. Thereaction mixture was filtered and concentrated in vacuo to leave a crudesolid (0.9g) that was analyzed by GC: 83% A. It was further purifiedthrough crystallization by dissolving in hexane (7 mL) at 50° C. andallowed to stand at room temperature for 5 h. The resulted solids werefiltered and dried in vacuo and the obtained solids of(R,S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine (225 mg) wasanalyzed by GC: 95% A. The racemic mixture was determined by chiralHPLC: 47:53 (R:S) and by specific rotation [α]D25-1.45, C=0.15% inmethanol.

The invention claimed is:
 1. A process for the preparation of(R,S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine having thefollowing Formula (I), starting with(S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine having thefollowing Formula (II),

comprising the steps of: (a) acylating the(S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine to obtain anindaneamide derivative; (b) oxidizing said indaneamide derivative toobtain 3-hydroxyl indaneamide derivative; (c) dehydrating said3-hydroxyl indaneamide derivative to obtain indeneamide derivative; (d)deacylating said indeneamide derivative to obtain indene aminederivative; and (e) hydrogenating said indene amine derivative to obtainthe desired (R,S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine.2. A process according to claim 1, which comprises:

(a) acylating the compound of Formula (II) with an acylating agent ofFormula RC(O)X to give a corresponding indaneamide derivative of Formula(III);

(b) oxidization of said indaneamide derivative to give the corresponding3-hydroxyl indaneamide derivative of Formula (IV)

(c) dehydration of said 3-hydroxyl indaneamide derivative to give thecorresponding indeneamide derivative of Formula (V);

(d) deacylation of said indeneamide derivative to give the correspondingindeneamine derivative of Formula (VI); and

(e) hydrogenation of said indeneamine derivative to obtain the desired(R,S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine,

wherein, R is selected from a C₁-C₆ alkyl group or a C₆-C₁₀ aryl group,these groups being optionally substituted with one or more of C₁-C₆alkyl groups and/or halogen atoms; X is a leaving group selected from:(i) a hydroxy group; (ii) a halogen atom; (iii) a C₁-C₆ alkylsulfonyloxygroup; (iv) a C₆-C₁₀ arylsulfonyloxy group, (v) a R_(a)COO group whereinR_(a) is a C₁-C₆ alkyl group, the groups (iii)-(v) being optionallysubstituted with one or more halogen atoms.
 3. The process according toclaim 1, wherein step (c) is carried out prior to or subsequent to step(d), or these two steps are carried out concurrently.
 4. The processaccording to claim 1, wherein said acylating agent RC(O)X is selectedfrom acyl halide and anhydride, preferably from acetyl chloride, aceticanhydride or mixture thereof.
 5. The process according to claim 1,wherein said step (a) is carried out at elevated temperature, preferablyranging from about 80° C. to about 120° C., more preferably from about80° C. to about 100° C.
 6. The process according to claim 1, whereinoxidization step (b) comprises reacting said indaneamide derivative inthe presence of oxidizing agent preferably selected from KMnO₄, MnO₂,SeO₂, CrO₃, or mixture thereof, to yield 3-hydroxyl indaneamidederivative.
 7. The process according to claim 1, wherein dehydrationstep (c) comprises reacting said 3-hydroxyl indaneamide derivativedissolved in an organic solvent, preferably a polar solvent, and morepreferably selected from hexane, heptanes, methylene chloride,dichloroethane, methanol, ethanol, isopropanol, toluene, ethyl acetateand mixtures thereof, in the presence of strong acid preferably selectedfrom HCl, HBr, H₂SO₄ or mixture thereof, to yield indeneamide.
 8. Theprocess according to claim 1, wherein the dehydration step (c) iscarried out at room temperature, preferably ranging from about 25° C. toabout 40° C.
 9. The process according to claim 1, wherein deacylationstep (d) comprises: contacting said indeneamide with a strong acid atelevated temperature to give an addition salt of indeneamine; and thensaid addition salt is treated with base solution to yield the desired(R,S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine.
 10. Theprocess according to claim 9, wherein the elevated temperature in step(d) is ranging from about 90° C. to about 120° C., more preferably fromabout 100° C. to about 120° C.
 11. The process according to claim 9,wherein the strong acid in step (d) is selected from HCl, HBr, H₂SO₄ andmixtures thereof.
 12. The process according to claim 9, wherein the basein step (d) is selected from Na0H, NaHCO₃, KOH and mixtures thereof. 13.The process according to claim 1, wherein said hydrogenation step (e)comprises: contacting said indeneamine dissolved in an organic solventwith gaseous hydrogen in the presence of a hydrogenation catalyst, toobtain the desired(R,S)-7-fluoro-1,1,3-trimethyl-2,3-dihydro-1H-inden-4-amine.
 14. Theprocess according to claim 13, wherein said organic solvent in step (e)is a polar solvent, and preferably selected from hexane, heptanes,methylene chloride, dichloroethane, methanol, ethanol, isopropanol,toluene, ethyl acetate and mixtures thereof.
 15. The process accordingto claim 13, wherein said hydrogenation catalyst in step (e) is Group(X) metal catalysts, preferably selected from nickel, palladium andplatinum and mixture thereof, more preferably Pd—C catalyst.